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Translational research

4576 - Biomarker prevalence study and Phase I trial of afatinib in children with malignant tumours


09 Sep 2017


Translational research


Cytotoxic Therapy;  Translational Research


Karsten Nysom


Annals of Oncology (2017) 28 (suppl_5): v22-v42. 10.1093/annonc/mdx363


K. Nysom1, P. Leblond2, D. Frappaz3, I. Aerts4, P. Varlet5, F. Giangaspero6, M. Gambart7, D. Hargrave8, L. Marshall9, P. Kearns10, G. Makin11, S. Gallego12, M. Kieran13, M. Casanova14, A. Lahogue15, S. Wind16, B. Stolze16, D. Roy17, M. Uttenreuther-Fischer18, B. Geoerger19

Author affiliations

  • 1 Department Of Paediatrics & Adolescent Medicine, Rigshospitalet, DK-2100 - Copenhagen/DK
  • 2 Centre Oscar Lambret, Unité d'oncopédiatrie, Lille/FR
  • 3 Centre Léon Bérard, Service Oncologie Pédiatrique, Lyon/FR
  • 4 Service De Pédiatrie, Institut Curie, Paris Cédex/FR
  • 5 Service De Neuropathology, Hôpital Sainte-Anne, Paris/FR
  • 6 Istituto Di Anatomia Patologica Policlinico Umbertoi, Università Roma Sapienza, Roma/IT
  • 7 Hôpital Des Enfants, CHU Toulouse, Toulouse/FR
  • 8 Haematology And Oncology Department, Great Ormond Street Hospital for Children, London/GB
  • 9 Children's And Young People's Unit, Royal Marsden NHS Foundation Trust, Sutton/GB
  • 10 Institute Of Cancer And Genomic Sciences, University of Birmingham, Birmingham/GB
  • 11 Department Of Paediatric Oncology, Royal Manchester Children's Hospital, Manchester/GB
  • 12 Servicio De Oncohematología Pediátrica, Hospital Vall d'Hebrón, Barcelona/ES
  • 13 Pediatric Oncology, Dana-Farber Cancer Institute, Boston/US
  • 14 Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan/IT
  • 15 Clinical Development, SCS Boehringer-Ingelheim Comm.V, Brussels/BE
  • 16 Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/DE
  • 17 Biostatistics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield/US
  • 18 Ta Oncology, Boehringer Ingelheim Pharma GmbH & Co. KG Biberach, Biberach/DE
  • 19 Department Of Pediatric And Adolescent Oncology, Gustave Roussy, Villejuif/FR


Abstract 4576


Dysregulation of the ErbB pathway may play a role in the development of paediatric neuroectodermal and mesenchymal tumours, suggesting that afatinib, an oral, irreversible ErbB family blocker, could be an effective treatment. A biomarker prevalence study assessed the frequency of ErbB-deregulations; in parallel, a Phase I trial (NCT02372006) was conducted.


Archived tissue samples from 277 neuroectodermal tumours and rhabdomyosarcomas were tested for protein expression of HER1–HER4, gene amplification of HER1/HER2 and mRNA expression of ErbB receptors and ligands. A Phase I afatinib trial in children aged 2 to 


In the biomarker prevalence study, ErbB deregulation markers were defined as: (A) HER1 gene amplification: HER1/Cen7 ≥2.0; ≥10% of cells with ≥15 copies; ≥40% of cells with ≥4 copies; or gene cluster in ≥ 10% of cells; (B) HER2 gene amplification: HER2/CEP17 ≥2.0; Protein expression (membrane); (C) EGFR H-score >150; and (D) HER2 H-score >0. Patients (pts) with tumours positive for ≥2 markers (A–D) will be selected to enrich the trial expansion cohorts. In the Phase I trial, 23 pts were screened, 17 treated and 12 evaluable for MTD. 1/7 pts experienced DLTs at 18 mg/m2 and 2/5 at 23 mg/m2. DLT events were decreased appetite, diarrhoea, dehydration, hypernatraemia, hypokalaemia, cheilitis, rash. Diarrhoea (12 pts) and dry skin (6 pts) were the most frequently reported drug-related AEs. Exploratory PK analysis suggested that exposure at 18 mg/m2 in children was in a similar range as in adults treated with 40 mg/d. 1 pt with ependymoma had stable disease for 8 treatment cycles.


Afatinib was tolerable in children, with a safety profile similar to adults. The MTD was established at 18 mg/m2/d and resulted in drug exposure considered effective in adults. The biomarker prevalence study identified exploratory screening markers being used to enrich patient selection in the ongoing expansion cohort.

Clinical trial identification


Legal entity responsible for the study

Boehringer Ingelheim


Boehringer Ingelheim


D. Frappaz: Advisory board: BMS. P. Varlet: Advisory board: Roche (Herby trial), Novartis (dabrafinib trial), Boehringer (afatinib trial), Nanostring Technologies. D. Hargrave: Payments for being part of an advisory board in relation to the development of afatinib in childhood cancer. S. Gallego: Advisory board: Loxo Oncology. M. Kieran: Advisory board for Afatinib but do not receive any funds or payments. M. Casanova: Advisory board: Boehringer Ingelheim Pharma GmbH & Co. KG, Roche, Lilly, Bayer, Loxo Oncology. A. Lahogue, S. Wind, B. Stolze, D. Roy, M. Uttenreuther-Fischer: Employee of Boehringer Ingelheim. B. Geoerger: Advisory board: Boehringer Ingelheim. All other authors have declared no conflict of interest.

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